Biology subjects

Enomoto, Y.

Publications and source records attributed to Enomoto, Y..

4 recordsLinked to original sources

bioRxiv2026

The CD112-TIGIT/PVRIG Axis Mediates NK Cell Evasion inDecitabine-Treated Acute Myeloid Leukemia Cells

Both drug resistance and immune evasion are considered to contribute to the persistence of residual AML cells and disease relapse. Natural killer (NK) cells play an important role in antileukemic immune surveillance and represent a key component of antitumor immunity in AML. Here, we investigated whether antileukemic drugs alter the susceptibility of surviving AML cells to natural killer (NK) cell-mediated cytotoxicity. AML cells surviving decitabine treatment became resistant to NK-92-mediated killing and showed marked upregulation of CD112. CD112 overexpression reduced NK-92-mediated cytotoxicity, whereas deletion of CD112 in AML cells or deletion of either TIGIT or PVRIG, two inhibitory receptors for CD112, in NK-92 cells restored cytotoxicity. Mechanistically, decitabine induced demethylation of two enhancer regions within the CD112 locus. Deletion of either enhancer attenuated CD112 upregulation, suggesting that enhancer demethylation contributes to decitabine-induced CD112 expression. Furthermore, antibody-mediated blockade of CD112 or combined blockade of TIGIT and PVRIG enhanced cytotoxicity against decitabine-treated AML cells. CD112 upregulation was also observed following azacitidine or cytarabine treatment, although the magnitude of induction varied across drugs and cell lines. These findings identify CD112 upregulation, which is associated with enhancer demethylation, as a mechanism of drug-induced immune evasion in AML and provide a rationale for combining hypomethylating agents with blockade of the CD112-TIGIT/PVRIG axis to enhance NK cell-mediated antileukemic activity.

cancer biology↗

bioRxiv2024

Development of the 12-base short dimeric myogenetic oligodeoxynucleotide that induces myogenic differentiation

A myogenetic oligodeoxynucleotide (myoDN), iSN04 (5-AGA TTA GGG TGA GGG TGA-3), is a single-stranded 18-base telomeric DNA that serves as an anti-nucleolin aptamer and induces myogenic differentiation, which is expected to be a nucleic acid drug for the prevention of disease-associated muscle wasting. To improve the drug efficacy and synthesis cost of myoDN, shortening the sequence while maintaining its structure-based function is a major challenge. Here, we report the novel 12-base non-telomeric myoDN, iMyo01 (5-TTG GGT GGG GAA-3), which has comparable myogenic activity to iSN04. iMyo01 as well as iSN04 promoted myotube formation of primary-cultured human myoblasts with upregulation of myogenic gene expression. Both iMyo01 and iSN04 interacted with nucleolin, but iMyo01 did not bind to berberine, the isoquinoline alkaloid that stabilizes iSN04. Nuclear magnetic resonance revealed that iMyo01 forms a G-quadruplex structure despite its short sequence. Native polyacrylamide gel electrophoresis and computational molecular dynamics simulation indicated that iMyo01 forms a homodimer to generate a G-quadru-plex. These results provide new insights into the aptamer truncation technology that preserves aptamer conformation and bioactivity for the development of efficient nucleic acid drugs. Key ContributionThis study reports the structure-based shortening of a myogenetic oligodeox-ynucleotide, iSN04, as an anti-nucleolin aptamer that induces myogenesis. The shortening technology of aptamers while maintaining their conformation and activity improves their potency of drug function and synthesis cost.

cell biology↗

bioRxiv2022

Exome-wide benchmark of difficult-to-sequence regions using short-read next-generation DNA sequencing

Next-generation DNA sequencing (NGS) in short-read mode has been recently used for genetic testing in various clinical settings. NGS data accuracy is crucial in clinical settings, and several reports regarding quality control of NGS data, focusing mostly on establishing NGS sequence read accuracy, have been published thus far. Variant calling is another critical source of NGS errors that remains mostly unexplored despite its established significance. In this study, we used a machine-learning-based method to establish an exome-wide benchmark of difficult-to-sequence regions using 10 genome sequence features on the basis of real-world NGS data accumulated in The Genome Aggregation Database (gnomAD) of the human reference genome sequence (GRCh38/hg38). We used the obtained metrics, designated "UNMET score," along with other lines of structural information of the human genome to identify difficult-to-sequence genomic regions using conventional NGS. Thus, the UNMET score could provide appropriate caveats to address potential sequential errors in protein-coding exons of the human reference genome sequence GRCh38/hg38 in clinical sequencing.

genomics↗

bioRxiv2022

Distinct super-enhancer elements differentially control Il2ra gene expression in a cell-type specific fashion

The IL-2 receptor -chain (IL-2R/CD25) is constitutively expressed on DN2/DN3 thymocytes and Treg cells but induced by IL-2 on mature T and NK cells. Il2ra expression is regulated by a super-enhancer extensively bound by STAT5 in mature T cells. Here, we demonstrate that STAT5 cooperates with Notch to induce/maintain Il2ra/CD25 expression in DN2/DN3 cells. Moreover, we systematically investigated CD25 regulation using a series of mice with deletions spanning STAT5 binding elements. Deleting the upstream super-enhancer region mainly affected constitutive CD25 expression on DN2/DN3 thymocytes and Tregs, whereas deleting an intronic region primarily decreased IL-2-induced CD25 on peripheral T and NK cells. Thus, distinct elements preferentially control constitutive versus inducible expression in a cell-type-specific manner, with the MED1 coactivator co-localizing with specific STAT5 binding sites. Moreover, the intronic region was a dominant element whose deletion altered the structure throughout the super-enhancer in mature T cells. These results demonstrate differential functions for distinct super-enhancer elements, thereby indicating ways to manipulate CD25 expression in a cell-type specific fashion.

immunology↗